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David C Whitcomb

Publications and source records attributed to David C Whitcomb.

At least 37 records · Page 2Linked to original sources
PubMed2005

Pancreatic response to endotoxin after chronic alcohol exposure: switch from apoptosis to necrosis?

Chronic alcohol consumption is known to increase the susceptibility to acute and chronic pancreatitis, and it is likely that a cofactor is required to initiate the progression to alcoholic pancreatitis. The severity and complications of alcoholic and nonalcoholic acute pancreatitis may be influenced by a number of cofactors, including endotoxemia. To explore the effect of a possible cofactor, we used endotoxin [lipopolysaccharide (LPS)] as a tool to induce cellular injury in the alcoholic pancreas. Single, increasing doses of endotoxin were injected in rats fed an alcohol or control diet and killed 24 h after the injection. We examined the mechanism by which LPS exacerbates pancreatic injury in alcohol-fed rats and whether the injury is associated with apoptosis or necrosis. We showed that chronic alcohol exposure alone inhibits apoptosis through the intrinsic pathway and the downstream apoptosis executor caspase-3 compared with the controls. Pancreatic necrosis and inflammation increased after LPS injection in control and alcohol-fed rats in a dose-dependent fashion but with a significantly greater response in the alcohol-fed animals. Caspase activities and TdT-mediated dUTP nick-end labeling positivity were lower in the alcoholic pancreas injected with LPS, whereas the histopathology and inflammation were more severe compared with the control-fed animals. Assessment of a putative indicator of necrosis, the ratio of ADP to ATP, indicated that alcohol exposure accelerates pancreatic necrosis in response to endotoxin. These findings suggest that the pancreas exposed to alcohol is more sensitive to LPS-induced damage because of increased sensitivity to necrotic cell death rather than apoptotic cell death. Similar to the liver, the pancreas is capable of responding to LPS with a more severe response in alcohol-fed animals, favoring pancreatic necrosis rather than apoptosis. We speculate that this mechanism may occur in acute alcoholic pancreatitis patients.

Adenosine Triphosphate↗
PubMed2005

Rapid adaptation of pancreatic exocrine function to short-term alcohol feeding in rats.

BACKGROUND: Chronic alcohol consumption increases the risk of pancreatitis in humans. Functional hyperstimulation/hypersecretion of the pancreas during chronic alcohol consumption appears to precede the onset of pancreatitis, and may contribute to the increased susceptibility to pancreatitis in alcoholics. However, the origin, nature and timing of hyperstimulation/hypersecretion are unknown. METHODS: Male Wistar rats were pair-fed ethanol liquid diet for 15-18 days (including one 9-day dose ramp-up phase) or regular liquid diets before placement of pancreatic, biliary, duodenal and venous catheters. Basal and stimulated pancreatic secretions were measured with or without acute alcohol infusion. Pancreatic secretion was stimulated with intravenous bethanechol, 2-deoxy-D-glucose (2-DG), cholecystokinin (CCK), octapeptide (CCK-8), intraduodenal meal, or vehicle. RESULTS: Acute alcohol potentiated 2-DG stimulated pancreatic secretion (184%, p < 0.05), whereas the response to CCK was unchanged, and the response to bethanechol was decreased (78%, p < 0.05). Short-term alcohol exposure lessened the exaggerated protein secretory response to 2-DG seen in acute alcohol exposure rats and increased the protein response to bethanechol (141%, p < 0.05), CCK (187%, p < 0.05) and meal (217%, p < 0.05). CONCLUSION: The pancreas is sensitive to acute alcohol ingestion with inhibition of acinar cell function. Rapid adaptation occurs with short-term alcohol feeding, resulting in an exaggerated response to cholinergic input at the acinar cells, plus disinhibition of CCK and meal-stimulated pancreatic secretion. The central response to 2-DG and CCK are similar to area postrema lesions. Adaptation appears to be in response to alcohol-associated inhibition of the neurohormonal stimulatory pathway and compensatory upregulation at the acinar cell level.

Adaptation, Physiological↗
PubMed2005

Evaluating disorders with a complex genetics basis. the future roles of meta-analysis and systems biology.

Growing evidence suggests that complex gene and environment interactions underlie a number of diseases including chronic inflammatory diseases of the digestive system. The rapid advances in information and technology provide opportunities to discover the risks or etiology for a variety of disorders within individual patients. However, the availability of new data and new technology has outstripped the conceptual framework of simple disorders and challenges current statistical approaches. Here we address the issues surrounding study design and sample size for complex genetic traits, with special attention to meta-analysis and systems biology. We conclude that meta-analysis should play a limited role in evaluating studies of complex genetic diseases. Instead, systems biology-based approaches should be developed to integrate multiple, focused, and mechanistic association studies with the goal of assisting in the risk assessment of patients on a person-by-person basis.

Forecasting↗
PubMed2005

Inflammatory markers of disease severity in acute pancreatitis.

To date, CRP remains the single standard biochemical marker for predicting the severity of AP. Because the combination of clinico-physiological scores and CRP provides good information at 48 hours, research has focused on the predictive ability of various markers when applied in the initial 24 hours after admission to the hospital. After detailed review of the literature, the authors conclude that there is no single tool that serves as the optimal predictor of severity. There are, however, data supporting the use of certain tests to improve upon the clinician's early predictive ability on the subsequent course of AP. These include an APACHE II score greater than seven, IL-6 at the time of admission, and urine TAP, urine trypsinogen-2,and serum PMN-elastase at 24 hours (Box 1). These markers will only be able to help the clinician's predictive ability if they can be performed locally and if the results can be available in a timely manner. Future research should focus on markers such as procalcitonin, IL-8, IL-I ra, sTNFR,CAPAP, PLA-2, novel markers, and the combined use of more than one marker. The conventional research approach in predicting severity used in the last15 years has limitations and appears to have reached its maximal potential. Novel conceptions and approaches, such as identification of genetic polymorphisms that predispose to severe course and complications of AP, are needed for a quantum step forward.

Acute Disease↗
PubMed2005

Chronic alcohol consumption accelerates fibrosis in response to cerulein-induced pancreatitis in rats.

Alcohol consumption is a risk factor for chronic pancreatitis (CP), but the mechanism in humans remains obscure because prolonged alcohol consumption in most humans and animal models fails to produce alcoholic chronic pancreatitis (ACP). We hypothesize that the process leading to ACP is triggered by a sentinel acute pancreatitis (AP) event; this event causes recruitment of inflammatory cells, which initiates fibrosis driven by the anti-inflammatory response to recurrent AP and/or chronic oxidative stress. The aim was to determine whether chronic alcohol consumption accelerates fibrosis in response to cerulein-induced pancreatitis in the rat. Wistar male rats were pair-fed control (C) or 5% ethanol (E) Lieber-DeCarli liquid diets. Animals were studied without pancreatitis (P0), with cerulein pancreatitis induced once (P1), or with cerulein-induced pancreatitis weekly for 3 weeks (P3). AP markers, inflammation, and fibrosis were measured histologically, by gene expression profiling and protein expression. Macrophage infiltration was reduced in EP0 versus CP0 rats, but the pattern was reversed after AP. Microabscess, severe necrosis, and early calcification were only induced in the EP3 rats. Fibrosis was significantly induced in the EP3 rats versus EP1, CP1, and CP3 by histology, hydroxyproline content, and mRNA expression for collagen alpha1(1) and procollagen alpha2(1). Proinflammatory cytokine mRNAs were up-regulated shortly after induction of AP, while the anti-inflammatory cytokines (interleukin-10 and transforming growth factor-beta) were strongly up-regulated later and in parallel with fibrogenesis, especially in the EP3 rats. Pancreatic fibrosis develops after repeated episodes of AP and is potentiated by alcohol. Expression of fibrosis-associated genes was associated with expression of anti-inflammatory cytokines in alcohol-fed rats.

Alcohol Drinking↗
PubMed2005

Is the monocyte chemotactic protein-1 -2518 G allele a risk factor for severe acute pancreatitis?

BACKGROUND & AIMS: Acute pancreatitis (AP) reflects the intensity of the inflammatory response and is divided into mild AP (MAP) or severe AP (SAP). Monocyte chemotactic protein-1 (MCP-1) gene expression is altered by an A/G polymorphism (-2518), with the G allele increasing MCP-1 production. Our aim was to determine whether the MCP-1 -2518 A/G polymorphism affects the severity of AP. METHODS: Seventy-seven consecutive patients and 116 controls were evaluated. The A/G genotype was evaluated by polymerase chain reaction amplification, restriction fragment length polymorphism, and DNA sequencing. MCP-1 serum levels were quantified using a fluorescence bead-based immunoassay. RESULTS: Sixty-three of 77 patients had MAP (82%) and 14 of 77 had SAP (18%). Patients with SAP had a significantly greater proportion of the G allele (12 of 14; 86%) than did control subjects (50 of 116; 43%) (odds ratio [OR], 7.9; 95% confidence interval [CI], 1.7-37, P < .003) or MAP patients (29 of 63; 46%) (OR, 7.0; 95% CI, 1.5-34; P < .007). Patients with pancreatitis and AA genotype had a low risk for SAP (OR, .13; 95% CI, .01-.61; P < .003). As predicted by the genotype, the serum MCP-1 levels were significantly higher in the SAP patients when compared with the MAP patients ( P = .002) and they also predicted death. CONCLUSIONS: MCP-1 -2518 G allele is a risk factor for severe AP. MCP-1 serum levels, measured early in the course of AP, appear to be an accurate predictor of severity of acute pancreatitis and death.

Acute Disease↗
PubMed2005

The role of pancreatic cyst fluid molecular analysis in predicting cyst pathology.

BACKGROUND & AIMS: Current methods to detect malignancy in mucinous cystic neoplasms of the pancreas remain inadequate. The role of detailed molecular analysis in this context was investigated. METHODS: Endoscopic ultrasound-guided pancreatic cyst aspirates were prospectively collected during a period of 19 months and studied for cytology, carcinoembryonic antigen level, and molecular analysis. Molecular evaluation incorporated DNA quantification (amount and quality), k-ras point mutation, and broad panel tumor suppressor linked microsatellite marker allelic loss analysis by using fluorescent capillary electrophoresis. The sequence of mutation acquisition was also calculated on the basis of a clonal expansion model, and comparison was made to the final pathology. RESULTS: Thirty-six cysts with confirmed histology were analyzed. There were 11 malignant, 15 premalignant, and 10 benign cysts. Malignant cysts could be differentiated from premalignant cysts on the basis of fluid carcinoembryonic antigen level (P=.034), DNA quality (P=.009), number of mutations (P=.002), and on the sequence of mutations acquired (P<.001). Early k-ras mutation followed by allelic loss was the most predictive of a malignant cyst (sensitivity, 91%; specificity, 93%). CONCLUSIONS: Malignant cyst fluid contains adequate DNA to allow mutational analysis. A first hit k-ras mutation followed by allelic loss is most predictive of the presence of malignancy in a pancreatic cyst. This approach should serve as an ancillary tool to the conventional work-up of pancreatic cysts. Cumulative amount and timing of detectable mutational damage can assist in diagnosis and clinical management.

Carcinoembryonic Antigen↗
PubMed2005

Genetic polymorphisms in alcoholic pancreatitis.

BACKGROUND: Chronic, excessive alcohol consumption is clearly associated with acute and chronic pancreatitis. However, both clinical and laboratory studies demonstrate that alcohol consumption alone does not directly cause alcoholic chronic pancreatitis. Growing evidence suggests that environmental and possibly genetic cofactors must also be present to overcome the redundant mechanisms protecting the pancreas from pancreatitis and facilitating complete recovery. METHODS: The SAPE hypothesis model was used to organize potential triggering factors, susceptibility factors and disease-modifying factors based on insights from animal studies. A systematic review of genetic studies on alcoholic pancreatitis was conducted and the results were analyzed in the context of animal studies. RESULTS: To date, no major genetic cofactors for susceptibility or progression have been identified in approximately 90% of cases of human alcoholic chronic pancreatitis. Mutations have been identified in the pancreatic secretory trypsin inhibitor gene (SPINK1) in about 8% of cases, and an excess in cystic fibrosis transmembrane conductance inhibitor (CFTR) gene variants have been reported, but the details of the complex genetics with CFTR have not been clarified. None of the polymorphisms in alcohol-metabolizing genes or detoxifying genes appear to explain pancreatic susceptibility. CONCLUSIONS: New, adequately powered genetic studies are needed. Several major genetic epidemiology studies are underway in both Europe and the United States to help determine why only a subset of alcoholics develop alcoholic chronic pancreatitis.

Acute Disease↗
PubMed2005

Feature Selection for Classification of SELDI-TOF-MS Proteomic Profiles.

BACKGROUND: Proteomic peptide profiling is an emerging technology harbouring great expectations to enable early detection, enhance diagnosis and more clearly define prognosis of many diseases. Although previous research work has illustrated the ability of proteomic data to discriminate between cases and controls, significantly less attention has been paid to the analysis of feature selection strategies that enable learning of such predictive models. Feature selection, in addition to classification, plays an important role in successful identification of proteomic biomarker panels. METHODS: We present a new, efficient, multivariate feature selection strategy that extracts useful feature panels directly from the high-throughput spectra. The strategy takes advantage of the characteristics of surface-enhanced laser desorption/ionisation time-of-flight mass spectrometry (SELDI-TOF-MS) profiles and enhances widely used univariate feature selection strategies with a heuristic based on multivariate de-correlation filtering. We analyse and compare two versions of the method: one in which all feature pairs must adhere to a maximum allowed correlation (MAC) threshold, and another in which the feature panel is built greedily by deciding among best univariate features at different MAC levels. RESULTS: The analysis and comparison of feature selection strategies was carried out experimentally on the pancreatic cancer dataset with 57 cancers and 59 controls from the University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, USA. The analysis was conducted in both the whole-profile and peak-only modes. The results clearly show the benefit of the new strategy over univariate feature selection methods in terms of improved classification performance. CONCLUSION: Understanding the characteristics of the spectra allows us to better assess the relative importance of potential features in the diagnosis of cancer. Incorporation of these characteristics into feature selection strategies often leads to a more efficient data analysis as well as improved classification performance.

Journal Article↗
PubMed2004

The functional angiotensin converting enzyme gene I/D polymorphism does not alter susceptibility to chronic pancreatitis.

CONTEXT: Alterations of the renin-angiotensin system have been implicated in the pathogenesis of various diseases. The angiotensin converting enzyme is a key enzyme in the renin-angiotensin system. A deletion polymorphism of a 287-bp fragment of intron 16 of the angiotensin converting enzyme gene allele results in higher levels of circulating enzyme. ACE deletion genotype has been linked to heart diseases, sarcoidosis and liver fibrosis. The pancreatic renin-angiotensin system plays a role in the development of pancreatic fibrosis and ACE inhibitors decrease pancreatic fibrosis in experimental models. OBJECTIVES: We investigated the frequency of the ACE gene insertion/deletion polymorphism in chronic pancreatitis patients and controls. PATIENTS: Subjects with familial pancreatitis (n=51), sporadic chronic pancreatitis (n=104), and healthy controls (n=163) were evaluated. MAIN OUTCOME MEASURE: The presence of ACE insertion/deletion polymorphism. RESULTS: The frequency of the ACE gene deletion allele was similar in familial pancreatitis (49.0%) sporadic pancreatitis (51.0%) and controls (55.8%). Furthermore, there was no significant difference in clinical features between patients with ACE-insertion or insertion/deletion genotypes vs. patients with ACE-deletion genotype. CONCLUSION: We conclude that the ACE deletion genotype does not make a significant contribution to the pathogenesis and the progression of chronic pancreatitis.

Adolescent↗
PubMed2004

Transforming growth factor-beta1, interleukin-10 and interferon-gamma cytokine polymorphisms in patients with hereditary, familial and sporadic chronic pancreatitis.

BACKGROUND: The genetic influence is undefined in about 40% of patients with hereditary and familial pancreatitis and in the majority of patients with sporadic chronic pancreatitis. The pathophysiological mechanisms underlying the progression from acute to chronic pancreatitis have not been clarified. Cytokines participate in the immunological progression of pancreatic inflammation and may play an important role in the development of pancreatic fibrosis. AIMS: We determined whether functional polymorphisms in the transforming growth factor-beta1 gene at positions -509, +869 (codon 10) and +915 (codon 25), in the interleukin-10 gene at position -1082, and in the intron 1 of the interferon-gamma gene at position +874 are associated with hereditary, familial or sporadic pancreatitis. METHODS: We investigated 78 patients with hereditary and familial pancreatitis and 62 patients with sporadic pancreatitis that were tested negative for cationic trypsinogen gene mutations, and 73 controls. Mutational analysis was performed by direct DNA sequencing or by amplification refractory mutational system polymerase chain reaction. We used the age at onset as marker of disease severity. RESULTS: The genotype frequencies were similar between patients and controls for all investigated cytokine polymorphisms (p > 0.05). We did not find an association between the different genotypes and the age at onset of the disease, and we did not detect different genotype distributions in patients with morphological alterations on pancreatic imaging after a disease duration of up to 5 years. CONCLUSION: These genetic variants do not play a dominant role in hereditary, familial or sporadic chronic pancreatitis.

Adolescent↗
PubMed2004

Diabetes mellitus in Tropical Chronic Pancreatitis Is Not Just a Secondary Type of Diabetes.

AIMS: In chronic calcific pancreatitis of the tropics, etiology and relationship to developing diabetes mellitus are unknown. Some consider these cases a straightforward secondary type of diabetes, while others suggest selective beta-cell impairment. Testing pancreatic function, we investigated whether selective beta-cell impairment triggers diabetes associated with tropical pancreatitis. METHODS: At a Bangladeshi research institute, 8 chronic tropical pancreatitis and no diabetes mellitus subjects, 14 fibrocalculous pancreatic diabetics and 27 matched healthy controls underwent arginine (endocrine pancreatic function) and secretin (exocrine pancreatic function assessment) stimulation tests. RESULTS: All patients with clinically-diagnosed, chronic pancreatitis demonstrated pronounced exocrine pancreatic dysfunction with beta-cell functioning differing significantly between the two groups. Compared to controls, patients having tropical pancreatitis and no diabetes showed normal plasma C-peptide values at baseline and after arginine stimulation, while fibrocalculous pancreatic diabetics demonstrated a typical diabetic pattern for plasma C-peptide levels. In contrast, pancreatic alpha-cell functioning (glucagon response to arginine) was preserved in both pancreatitis groups. CONCLUSION: A preserved pancreatic alpha-cell function in diabetics with advanced chronic pancreatitis of the tropics supports the concept of two different pathogenic mechanisms, one eliciting chronic pancreatitis and the other selective pancreatic beta-cell impairment and subsequent diabetes mellitus.

Adult↗
PubMed2004

Genetic analysis of the glutathione s-transferase genes MGST1, GSTM3, GSTT1, and GSTM1 in patients with hereditary pancreatitis.

BACKGROUND: Specific mutations in the cationic trypsinogen gene ( PRSS1) are disease-causing in patients with hereditary pancreatitis, but the genetic background still remains mysterious in about 40% of patients with the disease. It has been suggested that oxidative stress contributes to pancreatic damage. The glutathione s-transferases (GSTs) represent major detoxification enzymes that protect cells from oxidative stress. METHODS: In the present study we tested whether mutations in the MGST1 and GSTM3 genes or common deletions in the GSTT1 and GSTM1 genes are associated with hereditary pancreatitis. We analyzed the entire coding region of MGST1 and GSTM3 in 30 patients that were tested negative for PRSS1 mutations, and we studied 55 controls. For GSTT1 and GSTM1, we investigated 75 hereditary pancreatitis patients who had been tested negative for PRSS1 mutations, 135 hereditary pancreatitis patients with a PRSS1 mutation, and 183 controls. Patients were further subclassified with regard to age of onset of disease as a marker of severity. RESULTS: No mutation was found in the MGST1 gene. In the GSTM3 gene, we detected a homozygous 670G > A polymorphism (V224I) with similar frequencies in patients and controls. We found no difference in the frequencies of the GSTT1 and GSTM1 null genotypes between patients and controls, and we detected no differences in age of onset in patients with or without GSTT1 and GSTM1 deletions. CONCLUSIONS: We conclude that genetic alterations in the MGST1, GSTM3, GSTT1, and GSTM1 genes do not play a dominant role in hereditary pancreatitis.

Adolescent↗